title: Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: implications for Alzheimer's disease.
abstract: Three loci that modify β-amyloid (Aβ) accumulation and deposition in the brains of a mouse model of Alzheimer's disease have been previously described. One encompasses the Psen2 gene encoding presenilin 2, a component of the γ-secretase activity responsible for generating Aβ by proteolysis. We show that the activity of mouse Psen2, as measured by levels of mRNA accumulation, unexpectedly is heritable in the liver but not the brain, suggesting liver as the origin of brain Aβ deposits. Administration of STI571, a cancer therapeutic that does not cross the blood-brain barrier, reduced accumulation of Aβ in both the blood and the brain, confirming brain Aβ's peripheral origin and suggesting that STI571 and related compounds might have therapeutic/prophylactic value in human Alzheimer's disease. The genes Cib1 and Zfhx1b reside within the other modifier loci and also exhibit heritable expression in the liver, suggesting that they too contribute to Aβ accumulation.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA. gregorsutcliffe@aol.com
authors.forename: J Gregor
authors.initials: JG
authors.lastname: Sutcliffe
authors.forename: Peter B
authors.initials: PB
authors.lastname: Hedlund
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Thomas
authors.forename: Floyd E
authors.initials: FE
authors.lastname: Bloom
authors.forename: Brian S
authors.initials: BS
authors.lastname: Hilbush
mesh_terms: D000544:Alzheimer Disease / Q000097:blood* / Q000188:drug therapy / Q000473:pathology*; D016229:Amyloid beta-Peptides; D000818:Animals; D001549:Benzamides; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D010879:Piperazines / Q000627:therapeutic use; D053766:Presenilin-2 / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D016229:Amyloid beta-Peptides; D001549:Benzamides; D002135:Calcium-Binding Proteins; C491605:Cib1 protein, mouse; D018398:Homeodomain Proteins; D010879:Piperazines; D053766:Presenilin-2; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D012097:Repressor Proteins; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D000068877:Imatinib Mesylate